Compressed tablet formulation

ABSTRACT

This invention relates to a 50% drug loaded compressed tablet formulation for efavirenz. Efavirenz is a non-nucleoside reverse trancriptase inhibitor being studied clinically for use in the treatment of HIV infections and AIDS.

BACKGROUND OF THE INVENTION

[0001] This invention relates to a compressed tablet formulation forefavirenz, which is 50 percent by weight drug loaded and can optionallybe film coated. Efavirenz is a non-nucleoside reverse trancriptaseinhibitor being studied clinically for use in the treatment of HIVinfections and AIDS. A process for the manufacture of the compressedtablet is also disclosed.

[0002] The synthesis of efavirenz and structurally similar reversetranscriptase inhibitors are disclosed in U.S. Pat. Nos. 5,519,021,5,663,169, 5,665,720 and the corresponding PCT International PatentApplication WO 95/20389, which published on Aug. 3, 1995. Additionally,the asymmetric synthesis of an enantiomeric benzoxazinone by a highlyenantioselective acetylide addition and cyclization sequence has beendescribed by Thompson, et al., Tetrahedron Letters 1995, 36, 8937-8940,as well as the PCT publication, WO 96/37457, which published on Nov. 28,1996.

[0003] Additionally, several applications have been filed which disclosevarious aspects of the synthesisof(−)-6-chloro-4-cyclopropyl-ethynyl-4-trifluoromethyl-1,4-dihydro-2H-3,1-benzoxazin-2-oneincluding: 1) a process for making the chiral alcohol, U.S. Ser. No.60/035,462, filed Jan. 14, 1997; 2) the chiral additive, U.S. Ser. No.60/034,926, filed Jan. 10, 1997; 3) the cyclization reaction, U.S. Ser.No. 60/037,059, filed Feb. 12, 1997; and the anti-solventcrystallization procedure, U.S. Ser. No. 60/037,385 filed Feb. 5, 1997and U.S. Ser. No. 60/042,807 filed Apr. 8, 1997.

[0004] The compressed tablet is an improved formulation which allows oneto utilize a tablet over a capsule. The compressed tablet has beendemonstrated to have comparable bioavailability data to that seen withthe capsule. The key feature of the formulation is the use of asuperdisintegrant and disintegrant intragranularly to achieved abioequivalent formulation. The compressed tablet form was difficult tomanage as efavirenz is fragile and the drug loses crystallinity uponcompression. This was overcome by adding lactose extragranularly.

SUMMARY OF THE INVENTION

[0005] The instant invention relates to a compressed tablet of efavirenzwhich is a 50 percent drug loaded formulation.

[0006] The instant invention also relates to the process for manufactureof the compressed tablet using a wet granulation method.

DETAILED DESCRIPTION OF THE INVENTION

[0007] The instant invention relates to a compressed tablet of efavirenzformulation which is 50 percent by weight drug loaded and can optionallybe film coated.

[0008] The compressed tablet comprises: efavirenz, filler/disintegrant,superdisintegrant, binder, surfactant, filler/compression aid,lubricant, and solvent, wherein of efavirenz is about 50% by weight ofthe total composition of the compressed tablet.

[0009] The efavirenz concentration can be varied from about 1 to about75 % by changing the concentration of remaining excipients. Furthermore,changing the tooling can give a wide ranges of doses, e.g. a 20 mg dosein a 40 mg tablet, a 300 mg dose in a 600 mg tablet, or a 600 mg dose ina 1200 mg compressed tablet, with the same composition. Removing thelactose from the formulation gives about 70% drug in the formulationgiving a 600 mg dose in a 860 mg compressed tablet. These variations arevery straightforward to effect. This formulation will allow one toformulate efavirenz as a single 600 mg dose as an 860 mg compressedtablet, where as a capsule formulation requires the administration of atleast two capsules to dose with 600 mg of efavirenz.

[0010] The invention contemplates the use of any pharmaceuticallyacceptable fillers/compression aids, disintegrants, super-disintegrants,lubricants, binders, surfactants, film coatings, and solvents. Examplesof these components are set forth below and are described in more detailin the Handbook of Pharmaceutical Excipients, Second Edition, Ed. A.Wade and P. J. Weller, 1994, The Pharmaceutical Press, London, England.

[0011] Fillers and compression aid concentrations can be varied betweenabout 5% to about 80% to complement the drug amount. Examples offillers/compression aids include: lactose, calcium carbonate, calciumsulfate, compressible sugars, dextrates, dextrin, dextrose, calciumphosphate, kaolin, magnesium carbonate, magnesium oxide, maltodextrinmannitol, powdered cellulose, pregelatinized starch, and sucrose.

[0012] Examples of disintegrants include: alginic acid,carboxymethylcellulose calcium, carboxymethylcellulose sodium, colloidalsilicon dioxide, croscarmellose sodium, crospovidone, guar gum,magnesium aluminum silicate, methylcellulose, microcrystallinecellulose, polyacrilin potassium, powdered cellulose, pregelatinizedstarch, sodium alginate and starch.

[0013] Examples of fillers (also referred to as a diluent) include:calcium carbonate, calcium sulfate, compressible sugars, confectioner'ssugar, dextrates, dextrin, dextrose, dibasic calcium phosphatedihydrate, glyceryl palmitostearate, hydrogenated vegetable oil (typeI), kaolin, lactose, magnesium carbonate, magnesium oxide, maltodextrin,mannitol, polymethacrylates, potassium chloride, powdered cellulose,pregelatinized starch, sodium chloride, sorbitol, starch, sucrose, sugarspheres, talc and tribasic calcium phosphate.

[0014] Superdisintegrant concentration can be varied between about 1% toabout 20% to complement the drug amount and obtain reasonabledissolution. Examples of super-disintegrants include the disintegrantslisted above, carboxymethylcellulose sodium, croscarmellose sodium,povidone, guar gum, polacrilin potassium, and pregelatinized starch.

[0015] Binder concentration can be varied between 1 and 10% tocomplement the drug amount. Examples of binders include: acacia, alginicacid, carbomer, carboxymethylcellulose sodium, dextrin, ethylcellulose,gelatin, guar gum, hydrogenated vegetable oil (type I), hydroxyethylcellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose,liquid glucose, magnesium aluminaum silicate, maltodextrin,methylcellulose, polymethacrylates, povidone, pregelatinized starch,sodium alginate, starch, and zein.

[0016] Examples of surfactants comprises anionic and cationicsurfactants, such as sodium lauryl sulfate, docusate sodium (dioctylsulfosuccinate sodium salt), benzalkonium chloride, benzethoniumchloride, and cetrimide (alkyltrimethylammonium bromide, predominantlyC₁₄ alkyl).

[0017] Examples of lubricants include: calcium stearate, glycerylmonostearate, glyceryl palmitostearate, hydrogenated castor oil,hydrogenated vegetable oil, light mineral oil, magnesium stearate,mineral oil, polyethylene glycol, sodium benzoate, sodium laurylsulfate, sodium stearyl fumarate, stearic acid, talc and zinc stearate.

[0018] Examples of solvent comprises: water, ethanol or mixturesthereof.

[0019] The compressed tablet can also be film coated. Film coatconcentration can be varied up to about 10% to complement the drugamount, and preferably about 3.1% to about 3.3%. Film coatingsuspensions include combinations of one, two or three of the followingcomponents: carboxymethylcellulose sodium, carnauba wax, celluloseacetate phthalate, cetyl alcohol, confectioner's sugar, ethyl cellulose,gelatin, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropylmethylcellulose, liquid glucose, maltodextrin, methyl cellulose,microcrystalline wax, Opadry and Opadry II, polymethacrylates, polyvinylalcohol, shellac, sucrose, talc, titanium dioxide, and zein.

[0020] The preferred filler/disintegrant is microcrystalline cellulose.The preferred superdisintegrant is croscarmellose sodium. The preferredbinder is hydroxypropyl cellulose. A preferred surfactant is sodiumlauryl sulfate. The preferred diluent/compression aid is lactose hydrousspray dried. The preferred lubricant is magnesium stearate. Thepreferred solvent for formulating this compressed tablet is water. Thepreferred film coating comprises: hydroxypropylcellulose, hydroxypropylmethylcellulose, and titanium dioxide.

[0021] The 300 mg film coated efavirenz tablet contains: Ingredient Amtper tablet Percent w/w Core Tablet: efavirenz 300 mg 50 microcrystallinecellulose NF 120 mg 20 hydroxypropyl cellulose LF NF 19.2 mg 3.2croscarmellose sodium 30 mg 5 sodium lauryl sulfate 6 mg 1 lactosehydrous spray dried (EG) 118.8 mg 19.8 magnesium stearate (EG) 6 mg 1Film Coating Material per Tablet: 3.1% by wt hydroxypropyl cellulose LFNF 8.05 mg 1.4 hydroxypropyl methylcellulose USP 6CPS 8.05 mg 1.4titanium dioxide USP 3.1 mg 0.3 Tablet Weight: 619.2 mg

[0022] A process for the preparation of a 50% drug loaded compressedtablet comprising the following steps:

[0023] (a) blending efavirenz with a filler/disintegrant,super-disintegrant, binder and surfactant;

[0024] (b) adding at least 1.1% by weight of water per weight ofefavirenz to wet granulate the blended mixture to agglomerate themixture;

[0025] (c) drying the granulated mixture to a moisture content of about0% to about 10%;

[0026] (d) milling the dried mixture to granulate to a uniform size;

[0027] (e) blending the milled mixture with a filler/compression aid;

[0028] (f) lubricating the blended mixture with a lubricant; and

[0029] (g) compressing the lubricated mixture to a compressed tablet ofthe desired shape.

[0030] The process as recited above which comprises the additional stepof film coating the compressed tablet with a film coating suspension toproduce the desired film coated compressed tablet.

[0031] The process as recited above wherein the granulated mixture isdried to a moisture contant of about 2% to about 5%.

[0032] A process for the preparation of a 50% drug loaded compressedtablet comprising the following steps:

[0033] (a) blending efavirenz with microcrystalline cellulose, sodiumlauryl sulfate, hydroxypropyl cellulose and croscarmellose sodium;

[0034] (b) adding at least 1.1 weight % water per weight of efavirenz towet granulate the blended mixture for about 3 minutes to about 8 minutesto agglomerate the mixture;

[0035] (c) drying the granulated mixture to a moisture content of about2% to about 5%;

[0036] (d) milling the dried mixture to a granulate of about 250μ toabout 75μ;

[0037] (e) blending the milled mixture with lactose;

[0038] (f) lubricating the blended mixture with magnesium stearate;

[0039] (g) compressing the lubricated mixture to a compressed tablet ofthe desired shape; and

[0040] (h) film coating the compressed tablet with a film coatingsuspension to about 3.1% to about 3.3% of weight of compressed tablet.

[0041] The process as recited above wherein the blended mixture is wetgranulated for about 6 minutes.

[0042] The process as recited above wherein the film coating suspensioncomprising hydroxypropylcellulose, hydroxypropyl methylcellulose, andtitanium dioxide.

[0043] Wet granulation can be conducted using granulator mixers, such asa Fielder 10 L high shear granulator mixer, a drum or pan granulator,and a fluid bed granulator. Granulation can also be achieved byconducting dry granulation (without water) using a roller compactionprocess.

[0044] The drying step can be conducted using a Glatt WST-15 fluid beddrier or a tray drier.

[0045] The milling step can be conducted using mills such as a Comil ora Fitz mill.

[0046] The lubricating and blending steps can be conducted in aV-blender or a ribbon blender.

[0047] The compression step to form the tablet can be done a variety ofpresses including a beta press, single station F-press, the 6-stationKorsh, etc.

[0048] Film coating can be performed in a Glatt Column coater, a smallerHi-coater (9″-12″ pan), etc.

[0049] The formulation also is bioequivalent to a capsule with a smallerdose (200 mg), and more bioavailable than other tablet compositions. Theadvantages over the capsule include robust processing and sorting steps,smaller size with a larger dose, and market preference. The tabletcomposition also overcomes the expect loss of crystallinity of efavirenzby adding the lactose extra-granularly while maintaining the dissolutionprofile.

[0050] The increased drug loading often compromises the dissolutionprofile of the drug. This hurdle was overcome by including thesuper-disintegrant intragranularly, as well as the disintegrantintragranularly. The lactose was added extra-ganularly to maintain thecrystallinity of efavirenz.

[0051] This formulation was determined to be bioequivalent to thecapsule formulation being used in clinical trials. The wet granulationprocess has been used to optimize the formulation such that about 80%dissolution of the drug occurs within 10 minutes in a 1% Sodium Dodecylsulfate (SDS) solution, while stirring at a 50 rpm paddle speed.

[0052] Preparation of(−)-6-chloro-4-cyclopropylethynyl-4-trifluoromethyl-1,4-dihydro-2H-3,1-benzoxazin-2-one(currently referred to by its generic name efavirenz or code nameDMP-266).

[0053] Scheme 1 outlines the key steps in the synthesis of(−)-6-chloro-4-cyclopropylethynyl-4-trifluoromethyl-1,4-dihydro-2H-3,1-benzoxazin-2-one(efavirenz). The chiral addition step allows for the enantioselectiveaddition of the cyclopropylacetylide across the trifluoromethylketoneof 1. The p-methoxybenzyl (PMB)-protected amino alcohol, 2, produced isthen deprotected to give the amino alcohol, 3. The amino alcohol is thencyclized using a chloroformate and base to give efavirenz.

[0054] Scheme 2 outlines the preparation of efavirenz using analternative process which is a chiral addition reaction. The new chiraladdition reaction allows for the elimination of theprotection-deprotection sequence as outlined in Scheme 1.

[0055] Scheme 3 describes the process for the synthesis of the chiralintermediate used in the preparation of efavirenz. This reaction hasbeen demonstrated to work using about 1.2 equivalents ofcyclopropylacetylene and chiral additive, much lesss than the priormethods. The numerous chiral additives have been run and give highyields with a commerically available chiral ligand, such as N-methylephedrine and N-pyrrolidinyl norephedrine.

[0056] The cyclization of the amino alcohol, 3 to produce the1,4-dihydro-2H-3,1-benzoxazin-2-one, 4 is outlined in Scheme 4 below.The reaction can be carried out as a one-step process, or alternativelya two step process with the potential isolation of the intermediatecarbamate, 5 depending upon the chloroformate utilized. It has beendemonstrated that the aryl chloroformates form less stable carbamatessuch that when they are treated with aqueous base they cyclize to theproduct, in a one-step process. The alkyl chloroformate, alternatively,provides an alkyl carbamate, a key intermediate capable of beingisolated and purified prior to carrying out the cyclization step. Basedupon the stability of the alkyl carbamates, a viable two step processfor the preparation of efavirenz has been developed which comprises theformation of the alkyl carbamate intermediate, 5 followed by thecyclization of the carbamate to give the desired product, 4.Additionally, it has been demonstrate that phosgene can also be used.

[0057] The compressed tablet is formulated following the sequence ofsteps outlined in Scheme 5.

[0058] The following examples are meant to be illustrative of thepresent invention. These examples are presented to exemplify theinvention and are not to be construed as limiting the scope of theinvention.

EXAMPLE 1

[0059]

Materials Amount Mol MW Ketone 1a 1.00 kg g 4.47 223.58 (1R,2S)-N-pyrrolidinyl norephedrine 1.35 kg 6.58 205.30 cyclopropylacetylene 361.9 g 5.47 66.10 n-BuMgCl (2.0 M in THF) 2.68 L 5.372,2,2-trifluoroethanol (99%) 429.5 g 4.29 100.04 ZnEt₂ (0.892 M inhexane) 6.02 L 5.37 THF 9.36 L 30% K₂CO₃ 550 mL 30% citric acid 2.0 LToluene (for crystallization, 2 mL/g of 4) 2.6 L Heptane (forcrystallization, 4 mL/g of 4) 5.2 L

[0060] To a solution of trifluoroethanol and (1R, 2S)-N-pyrrolidinylnorephedrine in THF (9 L) under nitrogen is added a solution ofdiethylzinc in hexane at 0° C. slowly enough to keep the temperaturebelow 30° C. The mixture is stirred at room temperature for 0.5˜1 h. Inanother dry flask a solution of chloromagnesium cyclopropyl acetylide isprepared as follows: To neat cyclopropyl acetylene at 0° C. is added asolution of n-butylmagnesium chloride slowly enough to keep the internaltemperature ≦30° C. The solution is stirred at 0° C. for ˜40 min andtransfered to the zinc reagent via cannula with 0.36 L of THF as a wash.The mixture is cooled to −10° C. and ketoaniline 1a is added. Themixture is stirred at −2 to −8° C. for 35 h, warmed to room temperature,stirred for 3 h, and quenched with 30% potassium carbonate over 1.5 h.The mixture is stirred for 4 h and the solid is removed by filtrationand washed with THF (2 cake volume). The wet solid still contains ˜18 wt% of pyrrolidinyl norephedrine and is saved for further study. Thefiltrate and wash are combined and treated with 30% citric acid. The twolayers are separated. The organic layer is washed with water (1.5 L).The combined aqueous layers are extracted with 2.5 L of toluene andsaved for norephedrine recovery. The toluene extract is combined withthe organic solution and is concentrated to ˜2.5 L. Toluene iscontinuously feeded and distilled till THF is not detectable by GC. Thefinal volume is controlled at 3.9 L. Heptane (5.2 L) is added over 1 h.The slurry is cooled to 0° C., aged for 1 h, and filtered. The solid iswashed with heptane (2 cake volume) and dried to give 1.234 Kg (95.2%yield) of amino alcohol 3 as a white crystalline. The material is 99.8 A% pure and 99.3% ee.

EXAMPLE 2

[0061]

FW g mL mmol equiv amino alcohol 3 289 100 346 14-nitrophenylchloroformate 201.6 73.2 363 1.05 KHCO₃ 100 45 450 1.3 2NKOH 56 346 692 2.0 H₂O 654 MTBE 500

[0062] To a three necked round bottom flask, equipped with a mechanicalstirrer, nitrogen line, and thermocouple, was charged the solid aminoalcohol 3, MTBE (500 mL), and aqueous KHCO₃ (45 g in 654 mL H₂O). Solid4-nitrophenyl chloroformate was added, in 4 batches, at 25° C. Duringthe addition the solution pH was monitored. The pH was maintainedbetween 8.5 and 4 during the reaction and ended up at 8.0. The mixturewas stirred at 20-25° C. for two hours. Aqueous KOH (2N) was added over20 minutes, until the pH of the aqueous layer reached 11.0.

[0063] The layers were separated and 500 mL brine was added to the MTBElayer. 0.1 N Acetic acid was added until the pH was 6-7. The layers wereseparated and the organic phase was washed with brine (500 mL). At thispoint the mixture was solvent switched to EtOH/IPA and crystallized asrecited in Examples 5 and 6.

EXAMPLE 3

[0064]

FW g mL mmol equiv amino alcohol 3a 289 100 346 1 phosgene (20 wt % intoluene) 99 41 216 415 1.2 KHCO₃ 100 86.5 865 2.5 H₂O 500 Toluene 500

[0065] To a three necked round bottom flask, equipped with a mechanicalstirrer, nitrogen line, and thermocouple, was charged the solid aminoalcohol 3a, toulene (500 mL), and aqueous KHCO₃ (86.5 g in 500 mL H₂O).Phosgene solution in toulene was added at 25° C., and the mixture wasstirred at 20-25° C. for two hours.

[0066] The layers were separated and the organic phase was washed withbrine (500 mL). At this point the mixture was solvent switched toEtOH/IPA and crystallized as recited in Examples 5 and 6.

EXAMPLE 4

[0067]

FW g mL mmol equiv amino alcohol 3a 289 100 346 1 phosgene (gas) 99KHCO₃ 100 86.5 865 2.5 H₂O 500 MTBE 500

[0068] To a three necked round bottom flask, equipped with a mechanicalstirrer, nitrogen line, and thermocouple, was charged the solid aminoalcohol 3a, MTBE (500 mL), and aqueous KHCO₃ (86.5 g in 500 mL H₂O).Phosgene gas was slowly passed into the solution at 25° C., until thereaction was complete.

[0069] The layers were separated and the organic phase was washed withbrine (500 mL). At this point the mixture was solvent switched toEtOH/IPA and crystallized as recited in Examples 5 and 6.

EXAMPLE 5

[0070] Crystallization of efavirenz from 30% 2-Propanol in Water using aratio of 15 ml solvent per gram efavirenz Using Controlled Anti-SolventAddition on a 400 g Scale.

[0071] 400 g. of efavirenz starting material is dissolved in 1.8 L of2-propanol. The solution is filtered to remove extraneous matter. 1.95 Lof deionized (DI) water is added to the solution over 30 to 60 minutes.10 g. to 20 g. of efavirenz seed (Form II wetcake) is added to thesolution. The seed bed is aged for 1 hour. The use of Intermig agitatorsis preferred to mix the slurry. If required (by the presence ofextremely long crystals or a thick slurry), the slurry is wet-milled for15-60 seconds. 2.25 L of DI water is added to the slurry over 4 to 6hours. If required (by the presence of extremely long crystals or athick slurry), the slurry is wet-milled for 15-60 seconds during theaddition. The slurry is aged for 2 to 16 hours until the productconcentration in the supernatant remains constant. The slurry isfiltered to isolate a crystalline wet cake. The wet cake is washed with1 to 2 bed volumes of 30% 2-propanol in water and then twice with 1 bedvolume of DI water each. The washed wet cake is dried under vacuum at50° C.

EXAMPLE 6

[0072] Crystallization of efavirenz from 30% 2-Propanol in Water using aratio of 15 ml solvent per gram efavirenz Using a Semi-ContinuousProcess on a 400 g Scale.

[0073] 400 g. of efavirenz starting material is dissolved in 1.8 L of2-propanol. A heel slurry is produced by mixing 20 g. of Form IIefavirenz in 0.3 L of 30% (v/v) 2-propanol in water or retaining part ofa slurry from a previous crystallization in the crystallizer. Thedissolved batch and 4.2 L of DI water are simultaneously charged to theheel slurry at constant rates over 6 hours to maintain a constantsolvent composition in the crystallizer. Use of Intermig agitatorsduring the crystallization is preferred. During this addition the slurryis wet-milled when the crystal lengths become excessively long or theslurry becomes too thick. The slurry is aged for 2 to 16 hours until theproduct concentration in the supernatant remains constant. The slurry isfiltered to isolate a crystalline wet cake. The wet cake is washed with1 to 2 bed volumes of 30% 2-propanol in water and then twice with 1 bedvolume of DI water each. The washed wet cake is dried under vacuum at50° C.

EXAMPLE 7

[0074] Preparation of Amino Alcohol 3 and ee Upgrading—Through Process

Materials Amount Mol MW Ketone 1 1.00 kg 4.47 223.58 (1R,2S)-N-Pyrrolidinyl norephedrine 1.35 kg 6.58 205.30 Cyclopropylacetylene 361.9 g 5.47 66.10 n-BuMgCl (2.0 M in THF) 2.68 L 5.37Trifluoroethanol (99%) 429.5 g 4.29 100.04 ZnEt₂ (0.892 M in hexane)6.02 L 5.37 THF 9.36 L 30% K₂CO₃ 1.2 L 1 M Citric acid 3.5 L Heptane 12L Isopropyl acetate (IPAc) 40 L 12N HCl 405 mL 4.88 tert-Butyl methylether (MTBE) 6 L Toluene 6.25 L Na₂CO₃ 1.2 kg 11.25

[0075] A solution of diethyl zinc in hexane was added to a solution oftrifluoroethanol (429.5 g, 4.29 mol) and (1R, 2S)-N-pyrrolidinylnorephedrine (1.35 kg, 6.58 mol) in THF (9 L), under nitrogen, at 0° C.The resulting mixture was stirred at room temperature for approx. 30min. In another dry flask a solution ofchloromagnesiumcyclopropylacetylide was prepared as follows. To asolution of n-butylmagnesium chloride in THF (2 M, 2.68 L, 5.37 mol) wasadded neat cyclopropylacetylene at 0° C. keeping the temperature ≦25° C.The solution was stirred at 0° C. for 1-2 h. The solution ofchloromagnesiumcyclopropylacetylide was then warmed to room temperatureand was transferred into the zinc reagent via cannula over 5 minfollowed by vessel rinse with 0.36 L of THF. The resulting mixture wasaged at ˜30° C. for 0.5 h and was then cooled to 20° C. The ketoaniline1 (1.00 kg, 4.47 mol) was added in one portion as a solid, and theresulting mixture was stirred at 20-28° C. for 3 h.

[0076] The reaction was quenched with 30% aq. potassium carbonate (1.2L) and aged for 1 h. The solid waste was filtered and the cake waswashed with THF (3 cake volumes). The filtrate and wash were combinedand solvent switched to IPAc.

[0077] The IPAc solution of product 3 and pyrrolidinyl norephedrine waswashed with citric acid (3.5 L) and with water (1.5 L). The combinedaqueous layers were extracted with IPAc (2 L) and saved for norephedrinerecovery. To the combined organic layers was added 12N HCl (405 mL, 4.88mol), to form a thin slurry of the amino alcohol-HCl salt. The mixturewas aged for 30 min at 25° C. and was then dried azeotropically.

[0078] The slurry was aged at 25° C. for 30 min and filtered. The cakewas washed with 2.5 L of IPAc and dried at 25° C. under vacuum/nitrogenfor 24 h to give 1.76 kg of the wet HCl salt.

[0079] The salt was dissolved in a mixture of MTBE (6 L) and aq Na₂CO₃(1.18 kg in 6.25 L water). The layers were separated and the organiclayer was washed with 1.25 L of water. The organic layer was thensolvent switched into toluene.

[0080] Heptane (5 L) was added over 1 h at 25° C. The slurry was cooledto 0° C., aged for 1 h, and filtered. The solid was washed with heptane(2 cake volumes) and was dried to give 1.166 kg (90% overall yield) ofamino alcohol 3 as a white crystalline solid. Norephedrine recovery

[0081] The aqueous solution was basified to pH13 using 50% aq NaOH, andextracted with heptane (2 L). The heptane solution was washed with water(1 L) and concentrated to remove residual IPAc and water. The finalvolume was adjusted to about 3 L. The heptane solution was cooled to−20° C., aged for 2 h, and filtered. The solid was washed with coldheptane (1 cake volume) and dried to give 1.269 kg solid (94% recovery).

EXAMPLE 8

[0082] 50% Drug-Loaded Compressed tablet Of Efavirenz Ingredient Amt perbatch Core Tablet: efavirenz 950 g microcrystalline cellulose NF 380 ghydroxypropyl cellulose LF NF 60.8 g croscarmellose sodium 95 g sodiumlauryl sulfate 19 g lactose hydrous spray dried (EG)* 19.8% w/wmagnesium stearate (EG)* 1% w/w water 1.045 L Film Coating Material perTablet: 3.3% by wt of tablet hydroxypropyl cellulose LF NF 8.54 mg(2.5%) hydroxypropyl methylcellulose USP 6CPS 8.54 mg (2.5%) titaniumdioxide USP 3.42 mg (1%) water (94 %)

[0083] Efavirenz (950 g) was blended with microcrystalline cellulose(380 g) , sodium lauryl sulfate (19 g) , hydroxypropyl cellulose (60.8g) and croscarmellose sodium (95 g) in a Fielder 10 L high sheargranulator mixer for four minutes. At least about 1.1 weight % water perweight of efavirenz (1.045 L) was added to wet granulate the blendedmixture over about 6 minutes to about 8 minutes to agglomerate themixture using an appropriate spray nozzle. The granulated mixture isdried to a moisture content of about 2% to about 5% in a Glatt WST-15fluid bed drier. The dried mixture was milled using a 40 G round screenin a Comil. The milled mixture was blended in a V-Blender with lactosefor 4 minutes (calculated amount is the amount needed to make the finalcomposition contain 19.8% lactose by weight). The blended mixture waslubricated with magnesium stearate (calculated amount is the amountneeded to make the final composition contain 1% magnesium stearate byweight) in the V-Blender for 3 minutes. The lubricated mixture wascompressed using a beta press to give a compressed tablet of the desiredshape. The compressed tablets were film coated with an aqueous coatingsuspension that contains 2.5% hydroxypropyl cellulose (HPC); 2.5%hydroxymethylcellulose (HPMC); and 1% titanium dioxide (TiO₂) and 94%water by weight percent in a 19″ O'Hara pan coater to a coat weight ofabout 3.3% per tablet. Note that the coat is the dried form of thesuspension.

What is claimed is:
 1. A compressed tablet comprising: efavirenz, filler/disintegrant, superdisintegrant, binder, surfactant, diluent/compression aid, lubricant, and solvent, wherein efavirenz is about 50% by weight of the total composition of the compressed tablet.
 2. The compressed tablet, as recited in claim 1 , wherein the filler comprises: lactose, calcium carbonate, calcium sulfate, compressible sugars, dextrates, dextrin, dextrose, calcium phosphate, kaolin, magnesium carbonate, magnesium oxide, maltodextrin mannitol, powdered cellulose, pregelatinized starch, and sucrose.
 3. The compressed tablet, as recited in claim 2 , wherein the disintegrant and superdisintegrant comprise: alginic acid, carboxymethylcellulose calcium, carboxymethylcellulose sodium, colloidal silicon dioxide, croscarmellose sodium, crospovidone, guar gum, magnesium aluminum silicate, methylcellulose, microcrystalline cellulose, polyacrilin potassium, powdered cellulose, pregelatinized starch, sodium alginate and starch.
 4. The compressed tablet, as recited in claim 3 , wherein the binder comprises: acacia, alginic acid, carbomer, dextrin, ethylcellulose, gelatin, guar gum, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, liquid glucose, magnesium aluminum silicate, maltodextrin, methylcellulose, polymethacrylates, povidone, pregelatinized starch, sodium alginate, starch, and zein.
 5. The compressed tablet, as recited in claim 4 , wherein the surfactant comprises: sodium lauryl sulfate, docusate sodium, benzalkonium chloride, benzethonium chloride, and cetrimide.
 6. The compressed tablet, as recited in claim 5 , wherein the filler/compression aid comprises: calcium carbonate, calcium sulfate, compressible sugars, confectioner's sugar, dextrates, dextrin, dextrose, dibasic calcium phosphate dihydrate, glyceryl palmitostearate, hydrogenated vegetable oil (type I), kaolin, lactose, such as lactose hydrous spray dried, magnesium carbonate, magnesium oxide, maltodextrin, mannitol, polymethacrylates, potassium chloride, powdered cellulose, pregelatinized starch, sodium chloride, sorbitol, starch, sucrose, sugar spheres, talc and tribasic calcium phosphate.
 7. The compressed tablet, as recited in claim 6 , wherein the lubricant comprises: calcium stearate, glyceryl monostearate, glyceryl palmitostearate, hydrogenated castor oil, hydrogenated vegetable oil, light mineral oil, magnesium stearate, mineral oil, polyethylene glycol, sodium benzoate, sodium lauryl sulfate, sodium stearyl fumarate, stearic acid, talc and zinc stearate.
 8. The compressed tablet, as recited in claim 7 , wherein the solvent comprises: water, ethanol or mixtures thereof.
 9. The compressed tablet, as recited in claim 8 , wherein the filler/disintegrant is a microcrystalline cellulose.
 10. The compressed tablet, as recited in claim 9 , wherein the superdisintegrant is a croscarmellose sodium.
 11. The compressed tablet, as recited in claim 10 , wherein the binder is a hydroxypropyl cellulose.
 12. The compressed tablet, as recited in claim 11 , wherein the surfactant is a sodium lauryl sulfate.
 13. The compressed tablet, as recited in claim 12 , wherein the filler/compression aid is a lactose hydrous spray dried.
 14. The compressed tablet, as recited in claim 13 , wherein the lubricant is a magnesium stearate.
 15. The compressed tablet, as recited in claim 14 , comprising efavirenz, microcrystalline cellulose NF, hydroxypropyl cellulose LF NF, croscarmellose sodium, sodium lauryl sulfate, lactose hydrous spray dried (EG), and magnesium stearate (EG).
 16. The compressed tablet, as recited in claim 15 , containing about 300 mg of efavirenz, about 120 mg microcrystalline cellulose NF, about 19.2 mg hydroxypropyl cellulose LF NF, about 30 mg croscarmellose sodium, about 6 mg sodium lauryl sulfate, about 118.8 mg lactose hydrous spray dried (EG), and about 6 mg magnesium stearate (EG).
 17. A process for the preparation of a 50% drug loaded compressed tablet comprising the following steps: (a) blending efavirenz with a filler/disintegrant, super-disintegrant, binder and surfactant; (b) adding at least 1.1% by weight of water per weight of efavirenz to wet granulate the blended mixture to agglomerate the mixture; (c) drying the granulated mixture to a moisture content of about 0% to about 10%; (d) milling the dried mixture to granulate to a uniform size; (e) blending the milled mixture with a filler/compression aid; (f) lubricating the blended mixture with a lubricant; and (g) compressing the lubricated mixture to a compressed tablet of the desired shape.
 18. The process as recited in claim 19 which comprises the additional step of film coating the compressed tablet with a film coating suspension to produce the desired film coated compressed tablet.
 19. The process as recited in claim 18 wherein the granulated mixture is dried to a moisture content of about 2% to about 5%.
 20. A process for the preparation of a 50% drug loaded film coated compressed tablet comprising the following steps: (a) blending efavirenz with microcrystalline cellulose, sodium lauryl sulfate, hydroxypropyl cellulose and croscarmellose sodium; (b) adding at least 1.1 weight % water per weight of efavirenz to wet granulate the blended mixture for about 3 minutes to about 8 minutes to agglomerate the mixture; (c) drying the granulated mixture to a moisture content of about 2% to about 5%; (d) milling the dried mixture to a granulate of about 250μ to about 75μ; (e) blending the milled mixture with lactose; (f) lubricating the blended mixture with magnesium stearate; (g) compressing the lubricated mixture to a compressed tablet of the desired shape; and (h) film coating the compressed tablet with a film coating suspension to about 1% to about 10% by weight of the weight of compressed tablet.
 21. The process as recited claim 20 , wherein the blended mixture is wet granulated for about 6 minutes.
 22. The process as recited claim 21 , wherein the film coating suspension comprising hydroxypropylcellulose, hydroxypropyl methylcellulose, and titanium dioxide.
 23. The process as recited claim 22 , wherein the compressed tablet is film coated with the film coating suspension to about 3.1% to about 3.3% by weight of the weight of compressed tablet. 